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J Biol Chem, Vol. 273, Issue 36, 22913-22920, September 4, 1998

Cooperative Interaction between alpha - and beta -Chains of Hepatocyte Growth Factor on c-Met Receptor Confers Ligand-induced Receptor Tyrosine Phosphorylation and Multiple Biological Responses

Kunio Matsumoto, Hirofumi Kataoka, Kazuhiko Date, and Toshikazu Nakamura

From the Division of Biochemistry, Biomedical Research Center, Osaka University Medical School, Suita, Osaka 565-0871, Japan

Hepatocyte growth factor (HGF) is a heterodimeric molecule composed of the alpha -chain containing the N-terminal hairpin domain, four kringle domains, and the serine protease-like beta -chain. We prepared HGF/NK4 and HGF/beta from the entire HGF after single-cut digestion with elastase. HGF/NK4 contains the N-terminal hairpin and four kringle domains, while HGF/beta is composed of the C-terminal 16 amino acids of the alpha -chain and the entire beta -chain, linked by a disulfide bridge. HGF/NK4 competitively inhibited the binding of 125I-HGF to the receptor, and affinity cross-linking analysis indicated that HGF/NK4 alone can bind to the c-Met receptor. In contrast, HGF/beta alone did not competitively inhibit the binding of 125I-HGF to the receptor and did not bind to the c-Met/HGF receptor. Scatchard analysis and affinity cross-linking experiments indicated that HGF/beta specifically binds to c-Met in the presence of HGF/NK4 but not HGF/NK2. Neither HGF/NK4 nor HGF/beta alone induced mitogenic, motogenic (cell scattering), and morphogenic (induction of branching tubulogenesis) responses; however, HGF/beta did induce these biological responses in the presence of HGF/NK4. Consistent with these results, although neither HGF/NK4 alone nor HGF/beta alone induced tyrosine phosphorylation of the c-Met/HGF receptor, HGF/beta induced tyrosine phosphorylation of the receptor when c-Met/HGF receptor was occupied by HGF/NK4. These results indicate that HGF/beta binds to the c-Met/HGF receptor that is occupied by HGF/NK4 and induces receptor tyrosine phosphorylation and the subsequent biological activities of HGF. We propose that there exists a unique cooperative interaction between alpha - and beta -chains, this interaction leading to beta -chain-dependent receptor tyrosine phosphorylation and subsequent biological responses.

Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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